ABSTRACT There are 2 million new HIV infections in the world each year. Acquisition of HIV is only partially explained by exposure, behavior, and concurrent sexually transmitted infections. There is growing evidence that both local and systemic immune activation may make target cells more susceptible to HIV. Studies that have noted associations with immune activation and HIV acquisition have not been equipped to identify specific disease states that accompany these at- risk profiles. Because the latent HIV reservoir is established within days of infection, and susceptibility of HIV target cells is modified by immune activation, the inflammatory state at the time of HIV acquisition may modulate the quantity of cells at risk, and therefore the size of the latent HIV reservoir. We will identify inflammatory profiles that modulate risk of HIV acquisition and size of the latent viral reservoir among high-risk men who have sex with men (MSM) in an established cohort in Lima, Peru. We will attempt to determine the component causes of immune activation, including persistent and transient viral infections, alcohol and substance use, and sexual exposure that contribute to this high-risk immune activation. In this Peruvian cohort, HIV-negative MSM were followed with monthly visits, questionnaires, and banked blood samples. MSM who acquired HIV were enrolled in a follow-up study and received antiretroviral therapy (ART) immediately or after 24 weeks, and will continue to be followed for the next four years. In Aim 1, we will use a nested case-control design to compare cytokine profiles and a novel viral serologic assay (VirScan) from matching time-points in MSM who did and did not acquire HIV to evaluate predictors of HIV acquisition. In Aim 2, we will evaluate immune activation and viral infections present immediately prior to HIV acquisition as predictors for size of the latent viral reservoir in MSM who acquired HIV. We will build statistical models to describe the role of viruses and other component causes of immune activation on HIV acquisition and reservoir size, respectively. Innovations in our study include the addition of cutting edge technology to evaluate immune responses to known viral infections (VirScan) to multidimensional cohort data to better identify human and cellular susceptibility to HIV infection, and the ability to connect causes of inflammation and markers of immune activation within a very narrow exposure period prior to HIV acquisition. We expect that the results of this study will improve our understanding of the pathophysiology of HIV susceptibility and allow further work towards biomedical interventions to prevent HIV infection and modulate the latent HIV reservoir.